ClinVar Miner

Submissions for variant NM_000709.4(BCKDHA):c.647-1G>C

gnomAD frequency: 0.00001  dbSNP: rs753216964
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000498679 SCV000589622 pathogenic not provided 2019-05-21 criteria provided, single submitter clinical testing Canonical splice site variant predicted to result in an in-frame deletion of a critical region.; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 19715473, 28417071, 25525159, 29789446, 26901124, 31980395)
Labcorp Genetics (formerly Invitae), Labcorp RCV000670031 SCV000949048 pathogenic Maple syrup urine disease 2024-05-06 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 5 of the BCKDHA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BCKDHA are known to be pathogenic (PMID: 16786533, 22593002). This variant is present in population databases (rs753216964, gnomAD 0.0009%). Disruption of this splice site has been observed in individuals with maple syrup urine disease (PMID: 19715473, 31980395). This variant is also known as IVS5-1G>C. ClinVar contains an entry for this variant (Variation ID: 431985). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000670031 SCV001338325 pathogenic Maple syrup urine disease 2020-02-24 criteria provided, single submitter clinical testing Variant summary: BCKDHA c.647-1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 248460 control chromosomes. c.647-1G>C has been reported in the literature in individuals affected with Maple syrup urine disease (Strauss_2006, Georgiou_2009). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab RCV000670031 SCV002033406 pathogenic Maple syrup urine disease 2021-11-07 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000670031 SCV002060240 pathogenic Maple syrup urine disease 2021-11-16 criteria provided, single submitter clinical testing NM_000709.3(BCKDHA):c.647-1G>C is a canonical splice variant classified as pathogenic in the context of maple syrup urine disease type Ia. c.647-1G>C has been observed in cases with relevant disease (PMID: 19715473, 31980395, 28417071). Functional assessments of this variant are not available in the literature. c.647-1G>C has been observed in population frequency databases (ExAC: 0.002%). In summary, NM_000709.3(BCKDHA):c.647-1G>C is a canonical splice variant that has internal structural support for pathogenicity and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Revvity Omics, Revvity RCV000670031 SCV003813673 pathogenic Maple syrup urine disease 2021-12-21 criteria provided, single submitter clinical testing
Baylor Genetics RCV000670031 SCV004215890 pathogenic Maple syrup urine disease 2023-08-18 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV005018835 SCV005648302 likely pathogenic Maple syrup urine disease type 1A 2024-06-04 criteria provided, single submitter clinical testing

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